Antimicrobial N-Halamine Polymers and Coatings: A Review of Their

Review pubs.acs.org/Biomac

Antimicrobial N‑Halamine Polymers and Coatings: A Review of Their Synthesis, Characterization, and Applications Franck Hui†,‡ and Catherine Debiemme-Chouvy*,†,‡ †

CNRS, UPR 15 du CNRS, Laboratoire Interfaces et Systèmes Electrochimiques 4, Place Jussieu, 75252 Paris, France Université Pierre et Marie Curie, LISE, 4, Place Jussieu, 75252 Paris, France

‡

ABSTRACT: Antimicrobial N-halamine polymers and coatings have been studied extensively over the past decade thanks to their numerous qualities such as effectiveness toward a broad spectrum of microorganisms, long-term stability, regenerability, safety to humans and environment and low cost. In this review, recent developments are described by emphasizing the synthesis of polymers and/or coatings having N-halamine moieties. Actually, three main approaches of preparation are given in detail: polymerization, generation by electrochemical route with proteins as monomers and grafting with precursor monomers. Identification and characterization of the formation of the N-halamine bonds (>N−X with X = Cl or Br or I) by physical techniques such as Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), energy-dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS), and by chemical reactions are described. In order to check the antimicrobial activity of the Nhalamine compounds, bacterial tests are also described. Finally, some examples of application of these N-halamines in the water treatment, paints, healthcare equipment, and textile industries are presented and discussed.

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INTRODUCTION Nowadays, the need for antimicrobial agents or coatings to disinfect drinking water or surfaces in order to prevent infection due to microorganisms is huge. The increasing development of bacterial resistance to the most powerful antibiotics and of nosoconial infections1 are of great concern. By way of example, about 2 million people acquire bacterial infections in United States hospitals, with 90 000 deaths each year.2 Another fact is almost half of the people in developing countries suffer from water-related diseases, and more than 3 million people die annually from illnesses associated with unsafe drinking water due to the lack of disinfection.3 Therefore, numerous antimicrobial agents that can effectively inhibit the growth of microorganisms have been developed.4,5 Among them, biocidal polymers, such as N-halamine antimicrobial polymers, have been extensively studied over the past decade.6−24 In fact, Nhalamines have long-term stability in aqueous solution and in dry storage, effectiveness toward a broad spectrum of microorganisms, and they are less corrosive than sodium hypochlorite, weakly toxic, relatively cheap, and so forth. They are particularly efficacious, safe to humans, and environmentally friendly. The idea of N-halamine compounds was first proposed by Kovacic and co-workers, in 1969.25,26 An N-halamine compound can be defined as a compound containing one or more nitrogen−halogen covalent bonds that is usually formed by halogenation of imide, amide, or amine groups.27−29 An Nhalamine has biocidal properties thanks to the oxidation state +I of halide atoms in chloramine (>N−Cl) or bromamine (>N−Br) groups. The general structure of an N-halamine © 2013 American Chemical Society

compound is shown in Figure 1. The N-halamines can have inorganic groups (e.g., phosphate, sulfate) and organic groups

Figure 1. General structure of an N-halamine compound. R1, R2 = H or Cl or Br or inorganic group or organic group. X = Cl or Br or I.

(e.g., alkyl group, carbonyl group), which are referred to as inorganic and organic N-halamines, respectively (Figures 2 and 3). The halogen is generally chlorine, but it could also be bromine or iodine.6,30 These oxidizing halogens can act through direct transfer of active element to the biological receptor or through dissociation to free halogen in aqueous media. The formation of inorganic chloramines occurs by reaction between ammonia and hypochlorous acid as follows: NH3 + HOCl → NH 2Cl + H 2O

(1)

Received: December 21, 2012 Revised: January 15, 2013 Published: February 8, 2013 585

dx.doi.org/10.1021/bm301980q | Biomacromolecules 2013, 14, 585−601

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Actually, in the structure of all the N-halamine compounds, no H is in α of the N−X bond, except in the case of 6-phenyl1,3,5-triazinane-2,4-dione (Figure 4).17 However, its stability is quite good due to the aromatic ring.

Figure 4. Structure of 6-phenyl-1,3,5-triazinane-2,4-dione. Figure 2. Structure of some inorganic N-halamines.

NH 2Cl + HOCl → NHCl 2 + H 2O

(2)

NHCl 2 + HOCl → NCl3 + H 2O

(3)

For organic polymers, N-halamine moieties can be divided into cyclic and acyclic structures. Cyclic N-halamines31−34 are stable due to the absence of an α-hydrogen, which prevents αhydrogen dehydrohalogenation. Cyclic N-halamines are very efficient, broad-spectrum biocides that can last for a relatively long time. Organic N-halamines can be classed into three types: imide (−C(O)−NX−C(O)−), amide (−C(O)−NX−R) and amine (RR′−NX) N-halamines. The trend of their stability is determined by their structure.35,36 The stability (against hydrolysis) of chlorine from N-halamine structures in aqueous solutions follows such an order that is imide < amide < amine halamine.37 Their antimicrobial activities have an inverse trend: imide >amide ≫ amine N-halamine.35 Thus, their stability and their antibacterial activity are opposite. This stability trend is useful for the selection of an ideal biocidal material depending on the purpose. For example, if there is a need for rapid inactivation of microorganisms, imide N-halamine compounds should be used. However, if there is a need for long-term stability, then amine N-halamine seems to be the best choice. Some examples of cyclic N-halamines are given in Figure 5. More recently, the synthesis of polymers having acyclic Nhalamine moieties have been developed.38−48 These polymers were also able to provide durable and rechargeable biocidal functions. An example of a polymer bearing acyclic N-halamine

The preparation of organic chloramines or bromamines is illustrated below: RR′NH + X 2 → RR′NX + HX

(4)

RR′NH + HOX → RR′NX + H 2O

(5)

RR′NH + OX− → RR′NX + OH−

(6)

where R is an organic substituent, R′ is either an organic substituent or H, and X is Cl or Br. Among organic substituents, it has to be noted that hydantoin (imidazolidine-2,4-dione) and dimethylhydantoin (structures 1 and 2, respectively, in Figure 3) are basic moieties of many N-halamine polymers or coatings. The N-halamine stability depends notably on the existence or not of an α-hydrogen. Indeed in the presence of an α-hydrogen, a dehydrohalogenation process could take place according to: R1−NX −CH
N−X

X = Cl, Br (8)

In this Review, which mainly takes into account the publications of the past decade, we describe the recent developments in the field of N-halamines by emphasizing the synthesis of polymeric N-halamines, notably with proteins as monomers. The characterization methods of these biocidal materials are also described, and finally some applications are presented. I. Preparation of N-Halamine Polymers or Coatings. N-halamine polymers can be considered as the derivatization of polymeric materials with haloamine functional groups. They have received much attention during the past decade due to their great potential of applications. Generally, biocidal N-halamine polymers can be prepared three ways. The first approach is the polymerization of Nhalamine monomers or monomers bearing N−H function by 588


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Figure 9. LbL assembly process. Adapted with permission from ref 8. Copyright 2011 American Chemical Society.

Figure 10. SEM images obtained from SnO2 films deposited on glass (A) as-grown, (B) after polarization at 1.5 V/SCE for 2 h in 0.5 M NaCl + 1 mg/mL BSA solution. Scale bar: 1 μm. Adapted with permission from ref 62. Copyright 2007 American Chemical Society.

of N−H groups from one to three. The resulting copolymers were covalently coated onto cotton fabric via the siloxane groups. Their stability toward washing cycles was exceptional due to the advantage of the polymeric coatings tethering onto surfaces with multiple bonds. However, surfaces can also be coated by the layer-by-layer (LbL) assembly technique recently used for the first time by Cerkez et al. for N-halamine biocidal coatings.8 The principal of the LbL and the copolymers used are illustrated in Figure 9. Due to the fact that bleached cotton is inherently negatively charged as indicated by a negative zeta potential, positively charged N-halamine copolymers were able to be deposited without need of surface modification. In fact, since the charged copolymers are very soluble in water, coating via the LbL technique may have industrial potential for antimicrobial functional or multifunctional coating of textiles. Kocer61 has also prepared a series of water-dispersible biocidal polymers by copolymerization of the HA (Figure 8) with the sodium salt of 2-acrylamido-2-methylpropane sulfonic acid. The addition of the as-synthesized copolymers at a concentration of 1.5 wt % into a commercial water-based latex paint rendered the latter antimicrobial upon chlorination with dilute household bleach. I.2. Electrogeneration of Biocidal Coatings. Another original way to prepare organic coatings possessing antibacterial properties due to the presence of N-halamine groups is to modify proteins with hypochlorite or hypobromite ions generated by electrochemistry, notably at a tin oxide electrode, especially if the protein contains numerous amino acid residues

bearing amine group such as histidine or lysine, as it is in the case of the bovine serum albumin (BSA). Actually, in the presence of hypochlorous or hypobromous acid electrogenerated by anodic oxidation of chloride or bromide ions, respectively, Debiemme-Chouvy et al. have shown that there is polymerization of the protein leading to poly-BSA (pBSA) and to the formation of nanoclusters of modified proteins (Figure 10), i.e., proteins containing Cl or Br depending on the nature of the electrolyte used.62−65 When a Sb-doped SnO2 electrode is polarized in chloride/ bromine containing aqueous solution, chloride and/or bromide ions (X−) are oxidized at the electrode surface, and this leads to hypochlorous and hypobromous acid66 2X − → X 2 + 2e−

(9)

in water Cl2 and Br2 disproportionate into HOCl (at pH > 2.5) and HOBr (at pH > 5.7): X 2 + H 2O → HOX + X− + H+

(10)

Therefore, the chemical modification of the SnO2 surface during halide ion oxidation (reactions 9 and 10) is due to the reaction of hypohalogenous acid with the protein side-chains. Actually, during the process, two types of reaction occur: (i) oxidation of sulfur atoms and (ii) substitution of H of some amine/imine/amide functions. The oxidation and the halogenation of the protein side-chain take place according to the following reactions:67−70 589


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Figure 11. Preparation and probable structure of ACHT-immobilized cotton cellulose. Reprinted with permission from ref 48. Copyright 2006 Elsevier.

Figure 12. Admicellar polymerization of VBDMH on cellulose and its conversion to an N-halamine biocidal cellulose. Reprinted with permission from ref 14. Copyright 2007 Elsevier.

be performed by electrochemical route, i.e., by oxidation of chloride/bromide ions. I.3. Grafting or Coating Approach. A great number of biocidal polymers have been prepared by grafting or coating procedure.9,14,40,15−19,21−24,75−81 N-halamine precursors can be bonded to substrates via different tethering groups such as epoxide,57,82 hydroxyl groups (diol),15 and alkoxy silane (siloxane).7,31,54,56,83−88 Tan and Obendorf89 have described a two-step grafting procedure leading to the attachment of 2,2,5,5-tetramethylimidozalidin-4-one (TMIO, molecule 4 in Figure 5) hydantoin onto microporous polyurethane (PU) membrane. Upon chlorination, the grafted TMIO hydantoin structures were converted into N-halamines. Sun and co-workers48 have synthesized 2-amino-4-chloro-6-hydroxy-s-triazine (ACHT) through hydrolysis of 2-amino-4,6-dichloro-s-triazine. Then ACHT was immobilized onto cellulosic fibrous materials by a simple pad-dry-cure approach (Figure 11). After treatment with diluted chlorine bleach, the resulting fibrous materials could effectively prevent the formation of biofilm. Badrossamay and Sun have prepared biocidal polypropylene (PP) by incorporating onto its backbone the 2,4-diamino-6diallylamino-1,3,5-triazine as an N-halamine precursor9 as well as several acyclic N-halamine precursors such as acrylamide, methacrylamide, N-tert-butylacrylamide and N-tert-butylmethacrylamide.40

Cystein side‐chain oxidation: R−SH + 3HOX → R−SO2 −X + 2X− + 2H+ + H 2O (11)

Cystine oxidation:

R−S−S−R′ + 5HOX → R−SO2

−X + R′−SO2 −X + 3X − + 3H+ + H 2O

(12)

H substitution, N ‐halamine formation: R−NH 2 + HOX → R−NHX + H 2O

(13)

Reactions 11 and 12 yield sulfonyl chloride/bromide groups. These groups are at the origin of the protein aggregation, i.e., at the polymerization of the protein, which leads to pBSA. Indeed, protein aggregation has been explained by intermolecular sulphonamide formation from oxidized thiol (sulfonyl halide) and the amine group of proteins:71−73 R−SO2 −X + NH 2−R′ → R−SO2 −NH−R′ + X− + H+ (14)

Reaction pathways including this reaction have been proposed by Fu et al.73 It has been shown that the surfaces coated with chlorinated/ brominated pBSA are not colonized by bacteria.74 This process is environmentally friendly since it does not use any organic solvent, and the regeneration of the N-halamine groups could 590


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Figure 13. Structure of two N-halamine silanes. Adapted with permission from ref 17. Copyright 2009 Elsevier.

Figure 14. Strategy of designing bilayer antibacterial surface on substrates using spin coating and toluene solvent. Reprinted with permission from ref 20. Copyright 2011 Elsevier.

Worley et al.14 synthesized the monomer 3-(4′-vinylbenzyl)5,5-dimethylhydantoin (VBDMH) and coated it onto cotton fibers by admicellar polymerization using a cationic surfactant cetylmethylammonium bromide (CTAB) as shown in Figure 12. The researchers of this group15 have also prepared a rechargeable biocidal cellulose by coating an N-halamine precursor 3-(2,3-dihydroxypropyl)-5,5-dimethylimidazolidine2,4-dione onto cotton fabrics with the assistance of a crosslinking agent 1,2,3,4-butanetetra-carboxylic acid (BTCA). Sun and co-workers also successfully grafted polyacrylamide onto cotton fabrics by using BTCA as a cross-linker.16 Two novel silanes have been synthesized by Worley et al.:17 6-phenyl-3-(3′-triethoxysilyl propyl)-1,3,5-triazinane-2,4-dione (MTPTD) (Figures 4 and 13) and 6,6-dimethyl-3-(3triethoxysilylpropyl)-1,3,5-triazinane-2,4-dione (DMTPTD). These molecules have been coated onto the surface of silica gel particles and cellulose. Upon treatment by diluted sodium hypochlorite solutions, the resulting materials become effectively biocidal. They have a great stability and rechargeability following exposure to UV and ambient light.

To improve the chlorine resistance and antibiofouling property of reverse osmosis (RO) membranes, it is a challenge to realize high performance over a long period of operation for raw RO membranes, Wang et al.18,19 have modified the surface of aromatic polyamide RO membranes by grafting 3-allyl-5,5dimethylhydantoin (ADMH) and 3-monomethylol-5,5-dimethylhydantoin (MDMH) onto them. Due to the fact that the grafted ADMH and MDMH moieties have an N-halamine bond for biocidal effect and a sacrificial pendant group for chlorine attacks, membrane degradations by biofouling and free chlorine oxidation have been solved at the same time. Unlike the polymers containing reactive sites, such as hydroxyl groups in cellulose or amide groups in nylon, most polymers are inert. Therefore it could be complicated to chemically bind antimicrobial moieties on their surface. Chen and Han20 have developed an original technique to functionalize inert polymers to produce antibacterial surfaces without changing their bulk properties. The principle is to deposit a bilayer by spin coating. The design of antibacterial surface formation is illustrated in Figure 14. First, a polystyrene (PS) layer is deposited, then a poly(styrene-b-tert-butyl acrylate) 591


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Figure 15. Formation of thermoplastic semi-interpenetrating network. Red dots represent monomer acrylamide (AM) or methacrylamide (MAM) and cross-linker N,N-methylenebisacrylamide (MBA). Red lines represent cross-linked poly(acrylamide) or poly(methacrylamide). Reprinted with permission from ref 90. Copyright 2010 John Wiley and Sons.

Figure 16. Schematic illustration of the synthetic procedure of magnetic N-halamine nanocomposites. Reprinted with permission from ref 91. Copyright 2011 Elsevier.

some NH groups in amide bonds were transformed into Nhalamines, which provide a powerful antibacterial efficacy. This design concept should be applicable to inert polymer to acquire antimicrobial properties. Another method to modify chemically inert poly(ethylene terephthalate) (PET) or polypropylene (PP) has been reported

(PS-PtBA) block copolymer self-assembled at the surface is fabricated. Then, by exposure to trifluoroacetic acid (TFA), the ester groups of PtBA blocks were converted into reactive carboxylic acid groups for conjugation with tert-butylamine molecules via amide bonds using 2-chloro-4,6-dimethoxy-1,3,5triazine (CDMT) as the linker. Upon treatment by NaOCl, 592


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Figure 17. (A) Synthesis of 1-chloro-3-dodecyl-5,5-dimethylhydantoin (Cl-DDMH). (B) 1H NMR spectra of BD, DMH, DDMH and Cl-DDMH. Reprinted with permission from ref 98. Copyright 2006 American Chemical Society.

by Liu et al.78,79,90 The principle of this method, which leads to the formation of an interpenetrating network (IPN) is shown in Figure 15. It was used to immobilize cross-linked polyacrylamide (PAM) or polymethacrylamide (PMAM) onto the surface of chemically inert thermoplastic polymeric substrates (PP and PET). After being converted to N-halamine upon chlorination, the resulting materials exhibited a durable and potent antibacterial activity. Moreover, surface morphology, breathability, and the tensile strength of the polymers remained relatively unchanged due to the fact that the modification was limited to one side of the polymer fabrics. Therefore this

method could also be applied to other semicrystalline polymeric substrates without compromising their bulk properties. Antibacterial performances of N-halamine materials should strongly depend on their activated surface area. In other words, N-halamine materials with larger surface area can provide more N-halamine functional sites to contact the bacteria, rending them more efficient. Therefore, fabrication of nano N-halamine materials with large surface area is desirable. Thus, Chen and co-workers23,24,91 have prepared novel magnetically separable N-halamine nanocomposites for improving antibacterial 593


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application. The procedure is summarized in Figure 16. First, the iron oxide nanoparticles were modified by citric acid in order to get a good dispersibility, and they were encapsulated by tetraethoxysilane (TEOS) leading to magnetic silica nanoparticles. Then, the precursor of N-halamine, poly(3allyl-5,5-dimethylhydantoin-co-methylmethacrylate) (poly(ADMH-co-MMA) (see Figure 16), was grafted onto the surface of the nanoparticles, and finally the magnetic Nhalamine nanocomposites were obtained upon chlorination, which converted the amide groups of the hydantoin into Nhalamine structures. The antibacterial activity of these nanocomposites was enhanced compared with their bulk counterparts. Moreover, these nanoparticles can be separated easily and rapidly from the media within a short time under an external magnetic field. This particular structure of magnetic core and antibacterial shell would result in promising application in many areas. II. Characterization of N-Halamines. The formation of the N-halamine bonds (>N−X) can be identified by physical techniques such as Fourier transform infrared spectroscopy (FTIR),92,93 1H nuclear magnetic resonance spectroscopy (NMR),94 X-ray photoelectron spectroscopy (XPS),95,96 energy-dispersive X-ray spectroscopy (EDX),97 and by chemical reactions. II.1. Characterization by Physical Techniques. As already mentioned, the nitrogen−halogen bonds are obtained by the halogenation treatment of the corresponding N−H bonds. Therefore, the comparison of the different signals of these two bonds by the same technique generally allows their identification. For example, to follow the conversion reaction of 5,5-dimethylhydantoin (DMH) to 3-dodecyl-5,5-dimethylhydantoin (DDMH) and then to Cl-DDMH (Figure 17A), Chen and Sun98 used 1H NMR and FTIR analyses. In the NMR spectra (Figure 17B), there is an amide proton signal at 5.8 ppm for DMH and DDMH, which disappeared in the case of Cl-DDMH, indicating that the N−H bond in DDMH has been transformed into a N−Cl group. The FTIR spectra of DMH and DDMH exhibit a broad peak centered around 3280 cm−1, which is attributable to N−H stretching vibrations; this peak is no longer detected in the spectrum of Cl-DDMH, confirming the conversion of N−H into N−Cl. For Cl-DDMH, there are also two new bands at 758 and 735 cm−1 assigned to the N−Cl bond and the CO band shifts from 1782 and 1707 cm−1 in DDMH to 1794 and 1728 cm−1 in Cl-DDMH due to the breakage of the hydrogen bonding in the amide group present in the DDMH molecule. EDX is an analytical technique used for elemental analysis or chemical characterization of solid samples. Therefore, it can also be used to characterize the presence of a halogen (Cl at 2.6 keV, Br at 1.5 keV). An example of EDX analysis concerns the polymerization and chlorination/bromination of BSA at a SnO2 electrode in the presence of chloride/bromide ions (see section I.2.). After an anodic polarization in BSA-containing seawater, the SnO2 surface is coated with a granular deposit (Figure 18). The EDX spectrum has evidenced that for the treated electrode, the Sn signals are attenuated in comparison with the untreated electrode, indicating that the electrode is coated with a deposit composed of C, N, O, S, elements characteristic of the proteins and also Br and Cl. No Na is evidenced (1 keV), indicating that Cl and Br are linked to the organic matter. Additionally, in order to specify the chemical composition of the surfaces, XPS analyses can be also performed. Indeed it is a

Figure 18. EDX spectra obtained from SnO2 electrodes (A) without treatment and (B) after polarization at 1.5 V/ECS for 2 h in seawater containing 1 mg mL−1 BSA. Adapted from ref 64. Copyright 2011 Elsevier.

powerful technique that allows the analysis of only the surface of a solid, i.e., less than 10 nm in thickness. All the elements could be detected except H and He. Figure 19 shows the XPS

Figure 19. XPS spectra of (A) unchlorinated chitosan and (B) chlorinated chitosan using NaOCl solution (based on iodimetric titration, the chlorinated chitosan contained 3% of active chlorine). Reprinted with permission from ref 50. Copyright 2007 John Wiley and Sons.

spectra obtained for an unchlorinated sample of chitosan and for a chlorinated one following the reaction shown in Figure 7.50 Two photopeaks, Cl2s and Cl2p, appeared in the spectrum obtained from the chlorinated chitosan and indicated the conversion of some N−H into N−Cl. Notice that when the chlorinated agent is hypochlorite sodium, in order to be sure that Cl atoms are linked to N atoms, no Na should be detected (Na1s: 1070 eV). The halogenated pBSA obtained by polarization of SnO2 electrode in BSA-containing seawater was also analyzed by XPS. The survey spectrum shown in Figure 20 confirms that after the polarization, the electrode surface is coated with a film composed of C, N, O, S, Cl, and Br. By recording the high594


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Figure 20. XPS spectra from a SnO2 film after polarization at −1.5 V/SCE for 2 h in seawater containing 1 mg/L BSA. Adapted with permission from ref 64. Copyright 2011 Elsevier.

Figure 21. Chemical characterization of chloramines by TNB. Left: optical images of SnO2 films and cuvettes (1 cm) containing the TNB solution. (A) unmodified TNB solution. Top: before immersion of the SnO2 films coated with a large organic deposit. Bottom: sample (B) after a 3 h immersion of the SnO2 films polarized at 1.5 V/SCE in 0.5 M NaCl solution containing 1 mg/mL BSA; sample C is the same as sample B, but before immersion, the SnO2 film was dipped for 4 h in 0.1 M methionine solution. Right: Absorbance spectra of TNB solutions (cuvette length: 0.2 cm). Black lines: reference (from cuvette A); blue and red lines correspond to samples B and C, respectively. Solid and dotted lines: spectra recorded after 30 min and 3 h, respectively, of immersion of the SnO2 films. Reprinted with permission from ref 62. Copyright 2007 American Chemical Society.

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Figure 22. Biofilm controlling function of (a) the untreated PU film against Staphylococcus aureus, (b) the chlorinated PU−HDI−DMH film against S. aureus, (c) the untreated PU film against Escherichia coli, and (d) the chlorinated PU−HDI−DMH film against E. coli. Reprinted with permission from ref 101. Copyright 2011 Elsevier.

dithiobis(2-nitrobenzoic acid) (DTNB). For example, Figure 21 shows the optical absorbance spectra obtained for various SnO2 samples coated with modified pBSA.62 II.2.3. Iodometric/Thiosulfate Titration. Finally, the active chlorine (Cl(+I)) content of N-halamine polymers can be quantitatively determined by iodometric titration. First, iodide ions are oxidized by chlorine leading to the release of iodine, which is then titrated with thiosulfate:

energy resolution spectrum, it is possible to evidence various contributions for a given element (chemical shift). This is the case for Cl and Br. Indeed, the Cl2p and Br3d photopeaks have been fitted with two contributions, each contribution being composed of a doublet (2p3/2 and 2p1/2 ; 3d5/2 and 3d3/2) (Figure 20). One contribution was ascribed to >N−X and the other to −SO2−X.64,65 II.2. Characterization by Chemical Reactions. The presence of >N−Cl or >N−Br groups (haloamines) can be evidenced by various chemical reactions. II.2.1. Reaction with Methionine. It is well-known that methionine reacts with the chloramine according to99,100

>N−Cl + 2I− + H+ → >N−H + I 2 + Cl−

(17)

I 2 + 2S2 O32 − → 2I− + S4 O6 2 −

(18)

50

For example, Cao and Sun have determined the active chlorine content of the chlorinated chitosan by this method. The Cl content value (in at %) was calculated according to

>N−Cl + HO2 CCH(NH 2)CH 2CH 2SCH3 + H 2O → >N−H + HO2 CCH(NH 2)CH 2CH 2S(O)CH3 + Cl− + H+

(15)

Cl% =

Thus, after treatment in a methionine solution, the sample does not contain Cl linked to N anymore. Therefore this reaction can be used to specify that Cl or Br atoms detected by EDX, for example, are really linked to N atoms. After the methionine treatment, no more Cl or Br should detected. II.2.2. Reaction with 5-Thio-2-nitrobenzoic Acid (TNB). The presence of N-halamines can also be evidenced and quantified by the reaction with TNB, by measuring the bleaching of a TNB solution at 412 nm according to >N−X + 2TNB → >NH + DTNB + X− + H+

(V − V0) × N 35.45 × Cl × 100 WCl 2

where N is the concentration (in mol L−1) of the titrant sodium thiosulfate solution, V0 and VCl are the volumes (in L) of the solution consumed in the titration of the unchlorinated and chlorinated samples, respectively, and WCl is the weight (in g) of the chlorinated sample. II.3. Stability and Rechargeability of the N-Halamines. Generally, N-halamines possess long-term stability in aqueous solution and in dry storage. For example, Sun et al.101 have recently prepared a new N-halamine-based polymer (PU− HDI−DMH) by covalently linking an N-halamine precursor, DMH, (compound 2, Figure 3), onto PU using 1,6-hexamethylene diisocyanate (HDI) as the coupling agent. The

(16)

with X being Cl or Br. Actually, the yellow-colored TNB reacts with chloramines and bromamines to regenerate colorless 5,5′596


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coatings, some tests have to be conducted. Various methods could be used: bacteria suspension (stirred flask), blended agar, AATCC-100 “sandwich test” or use of a column filled with the biocidal materials. Very often the bacteria used for these tests are Escherichia coli, a gram-negative bacterium and/or Staphylococcus aureus, a gram-positive one.98,102 For viability test, the experimental conditions could be as follows:27 10 μL of bacteria suspension (108−109 colony forming units per milliliter (CFU/mL)) is placed onto the surface of the tested film (a few cm2) which is then “sandwiched” with another identical film. A sterile weight (100 g) is added onto the films to ensure sufficient contact. After various periods of contact time (5 min to 8 h), the whole “sandwich” is transferred into sterile sodium thiosulfate aqueous solution (0.03 wt %) to quench the active chlorines. The resulting solution is vortexed in order to separate the two films and sonicated for 5 to 10 min to remove the adherent cells into the solution. Obviously it is necessary to verify, using a film without biocide, that the sonication/quenching treatment does not affect the growth of the bacteria. Then an aliquot of the solution is serially diluted and 100 μL of each dilution is plated onto agar plates. Finally, after incubation at 37 °C for 24 h, bacterial colonies on the agar plates are counted. The mode of action of the N-halamine polymers has been described by some researchers as direct transfer of oxidative halogen (Cl(+I) or Br(+I)) from the haloamine groups to the cell wall of the microorganism by direct contact followed by oxidation, rather than dissociation of Cl(+I) or Br(+I) into water followed by diffusion over to the microorganism.83,103−105 However, other researchers have evidenced, notably using the Kirby−Bauer test,106 that both processes take place.6,28,48,101 III. Applications. As already mentioned, the antimicrobial N-halamines have a broad application in many fields such as water disinfection, 4 , 3 5 , 1 0 7 , 1 0 8 paints, 5 2 , 6 1 , 1 0 9 healthcare,42,46,101,110 textiles,4,57,111−113,85,86,114−116 and so on. For water treatment, chlorine or water-soluble disinfectants are often used.117 However, by reacting with organic substances, free chlorine can yield trihalomethane analogues, which are suspected of being carcinogenic. One approach to avoid these drawbacks is the use of insoluble disinfectants such as N-halamines that are able to inactive microorganisms without releasing any toxic chemicals to the water to be treated. A great number of N-halamines have been prepared and, notably, N-halamine polymers that are elaborated in the form of highly cross-linked porous beads that can be packed into glass columns that could function as a cartridge filter.28,107,108 Tests have showed that N-halamine polymer beads are able to exhibit complete inactivation of S. aureus and E. coli in the contact time interval of 1−2 s.107 Therefore, these polymeric beads are particularly useful in the disinfection of potable water through cartridge fillers containing them. Recently, Ahmed et al.108 developed a new cross-linked Nhalamine polymer, polyepicyanuriohydrin, which has a good antimicrobial activity against viruses and bacteria. This polymer was already used successfully for water purification at a laboratory scale (Figure 24). Using specifically a column containing a nonhalogenated polymer to act as a trap for the halogen released from the main column, halogen was therefore absent in the water outlet from the station. A water purification station of industrial scale based on multifiltration technology was suggested to be established on using chlorinated crosslinked polyepicyanuriohydrin polymer.

antimicrobial activity of this polymer was very efficient (see Figure 22) and was unchanged at the end of the tests. It is noticeable that 91% of the original active chlorine were retained after 6 months of dry storage in the open air (see Table 1). Table 1. Durability and Rechargebility of the N-Halamines in the Chlorinated HDI−DMH−PUa sample fresh samples after six-month of storage after 10 cycles of “quenching− recharging” a

chorine atom area density (atoms/cm2)

chlorine left (%)

(1.76 ± 0.11) × 1016 (1.61 ± 0.23) × 1016 (1.74 ± 0.21) × 1016

100 91 98.6

Reprinted with permission from ref 101. Copyright 2011 Elsevier.

Moreover, the chlorine contents and antimicrobial activities were almost unchanged after 10 cycles of “quenching− recharging” treatment, indicating the good rechargeability of the antimicrobial function of the PU−HDI−DMH film. Another important parameter for applications of the Nhalamine biocidal polymers is their stability under UV light. Worley et al.45 studied the UVA light stability of acyclic Nhalamine polymeric films, poly(VAc-co-AM) and poly(VAc-coMAM), which were obtained by copolymerizing vinyl acetate (VAc) with an acyclic amide monomer, acrylamide (AM) and methacrylamide (MAM), respectively (Figure 6, R = H and R = CH3, respectively). The chlorine on the films decreased rapidly in the first hours of UVA irradiation, but only a slight decrease was observed with further irradiation time as shown in Figure 23. Moreover, 91% of chlorine was regained after one cycle of

Figure 23. UVA light stability of chlorinated poly(VAc-co-AM) (circle) and poly(VAc-co-MAM) (square). Cl(+I) initial concentration: 4.35 × 1017 at/cm2 and 4.15 × 1017 at/cm2, respectively. Open scatters: after rechlorination. Data are from Table 6 of ref 45.

rechlorination by household bleach. This indicates that the copolymers themselves were very stable under UVA light irradiation. In all cases, it is obvious that the process consumes chlorines or bromines. However, as already mentioned the consumed chlorines/bromines can be readily recharged by an halogenation treatment performed by exposure of the polymer to an aqueous solution containing chlorine/bromine donors (eq 8). II.4. Bioactivity of the N-Halamines. Obviously, to confirm the antimicrobial properties of the N-halamine polymers or 597


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Figure 24. Example of design for a large-scale water purification system based on multifiltration technology. Column 2 is filled with the N-halamine copolymer depicted in the frame. Adapted with permission from ref 108. Copyright 2011 American Society for Microbiology.

As far as paint applications are concerned, using for the first time a chlorinated monomer, N-chloro-2,2,6,6-tetramethyl-4piperidinyl methacrylate (Cl-TMPM) (clear liquid at room temperature), Cao and Sun52 have successfully prepared poly(Cl-TMPM) latex emulsions. Small amounts of this emulsion were added into a commercial water-based latex paint. The properties of these new paints were excellent: antimicrobial effects against bacteria (including multidrug resistant species), fungi, and viruses and prevention of bacteria biofilm formation on the paint surfaces. Moreover, it has been shown that the antimicrobial activity was long-lasting (more than 1 year). More recently, Kocer et al.61,109 have also developed biocidal paints but with a post chlorination step, i.e., the halogenation was performed after the drying of the paint. To check the stability of these films of the N-halamine paint, they were exposed to fluorescent and UVA lights. The stability of the N−Cl bond toward these lights irradiation was high, and the remaining chlorine loadings on the treated paints were sufficient to provide an antimicrobial property even after 8 weeks of light exposure. The treated paints can be rechlorinated

to about their initial chlorine loadings, indicating their good stability. With regard to healthcare applications, Sun et al.46 have developed a simple and practical surface grafting approach which permits one to introduce rechargeable N-halamine-based antimicrobial functionality onto the inner surfaces of continuous small-bore PU dental unit waterline tubing. In this approach, a tetrahydrofuran solution of dicumyl peroxide was used as a free-radical initiator in the subsequent grafting polymerization of methacrylamide (MAA) onto the inner walls of the tubing. The amide groups of the grafted MAA side chains were transformed into acyclic N-halamines upon chlorine bleach treatment. The biofilm formation inside the PU tubing was completely prevented for more than 3 weeks. Obviously, after many applications, the antimicrobial property of the tubing inner surface could be fully regenerated by household bleach leading to further extension of the biofilm-controlling duration for long-term applications. Very recently it has been shown that it is also possible to covalently link DMH to the surface of PU by using 1,6-hexamethylene diisocyanate as a coupling agent.101 Upon bleach treatment, the covalently 598


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bound DMH moieties were transformed into N-halamines, which provided powerful, rechargeable, and durable antimicrobial activities against not only Gram-positive and Gramnegative bacteria, but also drug-resistant bacteria and fungi. In fact, a stability of more than 6 months has been obtained as to the antimicrobial and biofilm-controlling effects. According to the Kirby−Bauer test, it has been shown that the antimicrobial function was at least partly due to the positive chlorines generated from the disassociation of the N-halamine structures. Finally, for textile applications, a great number of textiles and fibers have been modified by N-halamine functional groups, by means of copolymerization of polymerizable N-halamines with fabrics, cellulose, or by treating materials (paper, cotton, silica gel, cellulose) providing them with antimicrobial properties. For instance, Worley et al.15 have synthesized an N-halamine precursor, 3-(2,3-dihydroxypropyl)-5,5-dimethylimidazolidine2,4-dione, which contains two hydroxyl groups that can be chemically bonded onto cotton fabrics by using BTCA as a cross-linking agent.16,77,118 Indeed cotton cellulose, which has numerous hydroxyl groups, reacts with BTCA by forming ester bonds. Then the N-halamine precursor can react with BTCA through esterification. The amide nitrogen of the hydantoin rings could finally be converted to N-halamines upon exposure to dilute household bleach. The cotton fabrics acquired antimicrobial properties, and the treated cotton swatches showed excellent biocidal efficacy. It has been shown that over 70% of the chlorine lost after repeated washing or UVA irradiation could be restored upon chlorination treatment. Another route to render cotton antimicrobial is the synthesis of an N-halamine siloxane monomer precursor, which allows the silanol groups to react with the cellulose to form a nanocomposite coating.10,76,86,87 Moreover, it has been evidenced that preparation of a series of copolymers incorporating N-halamine siloxane and quaternary ammonium salt siloxane enhances the antimicrobial action of these agents in combination.105

chemistry and natural monomers or polymers should be employed for synthesis of new N-halamine (co)polymers or coatings so that they could be biocompatible. Finally, it should be kept in mind that for a real application, newly developed biocidal polymers must be cost-effective with an efficacious contact time of seconds.

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AUTHOR INFORMATION

Notes

The authors declare no competing financial interest.

REFERENCES

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CONCLUSIONS AND FUTURE PROSPECTS N-halamine polymers or coatings are promising antimicrobial materials conjugating efficiency, wide applicability, low toxicity, and regenerability. During the past five years, a lot has been done concerning, on one hand, the synthesis of new Nhalamines and, on the other hand, the development of their applications due to the increasing spread of microorganisms and of contaminated surfaces leading to medical and health issues and the huge need of drinking water. Among different synthesis methods of N-halamines, the elaboration by electrochemical routes such as the electrochemical modification and polymerization of proteins leading to water-insoluble nanoparticles is important as they are environmentally friendly and easy to practice. Even though some works in the mechanism of N-halamines against bacteria have been undertaken, further studies should be carried on so that new insights into their antimicrobial action could be obtained notably by using modern biophysical techniques. These results would be helpful for the design and synthesis of innovative N-halamine antimicrobial polymers that are safe to environment and to humans. In the future, new approaches should be developed. For instance, covalent surface grafting of >NH moieties (without H atom in alpha to avoid hydrolysis) by chemical or electrochemical routes following by the halogenation would allow one to render most surfaces antimicrobial. Moreover, green 599


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